High prevalence of vitamin A deficiency and vitamin D deficiency in patients evaluated for liver transplantation.
Deficiencies in vitamins A, D, and E have been linked to night blindness, bone health, and post-liver transplant reperfusion injury. The aim of this study was to determine the prevalence and predictive factors of fat-soluble vitamin deficiencies in liver transplant candidates. We reviewed the medical records of liver transplant candidates at our center from January 2008 to September 2011. The etiology of cirrhosis, Model for End-Stage Liver Disease score, Child-Pugh class, body mass index (BMI), and vitamin A, vitamin E, and vitamin 25-OH-D levels were recorded. Patients were excluded for incomplete laboratory data, short gut syndrome, celiac disease, pancreatic insufficiency, or prior liver transplantation. Sixty-three patients were included. The most common etiologies of liver disease were alcohol (n = 23), hepatitis C virus (n = 19), and nonalcoholic steatohepatitis (n = 5). Vitamin A and D deficiencies were noted in 69.8% and 81.0%, respectively. Only 3.2% of the patients were vitamin E-deficient. There were no documented cases of night blindness. Twenty-five of the 55 patients with bone density measurements had osteopenia, and 10 had osteoporosis. Four patients had vertebral fractures. There was 1 case of posttransplant reperfusion injury in a patient with vitamin E deficiency. In a multivariate analysis, there were no statistically significant predictors for vitamin D deficiency. The Child-Pugh class [odds ratio (OR) = 6.84, 95% confidence interval (CI) = 1.52-30.86, P = 0.01], elevated total bilirubin level (OR = 44.23, 95% CI = 5.02-389.41, P < 0.001), and elevated BMI (OR = 1.17, 95% CI = 1.00-1.36, P = 0.045) were found to be predictors of vitamin A deficiency. In conclusion, the majority of liver disease patients evaluated for liver transplantation at our center had vitamin A and D deficiencies. The presence or absence of cholestatic liver disease did not predict deficiencies, whereas Child-Pugh class, bilirubin level, and elevated BMI predicted vitamin A deficiency.


Islamic bioethics: a general scheme.
No doubt life in its all forms enjoys a very high status in Islam. Human life is one of the most sacred creatures of God. Therefore, it must be appreciated, respected and protected. In this regard, the paper refers to different parts. The first part studies the value of life in Islam. It helps to understand why life must be appreciated and respected. The second part sheds some light on the nature of the Islamic bioethics. Discussing the sources and authorities in the Islamic bioethics, in this part we will study the way of life protection which is regulated by the Islamic law and bioethics. Part three reflects on some important issues in bioethics from an Islamic perspective. Concerning the Islamic believes, physical health maintenance and disease treatment are two important aspects of the Islamic teachings. In respect to the beginning of human life; firstly, we will see that reproduction must occur in the context of a legitimate and stable family. Secondly, we will study family planning and abortion. With respect to the end of life, issues such as suicide and euthanasia will be studied. Finally organ transplantation will be discussed.


A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21) modified with polyethylene glycol.
As one of fibroblast growth factor (FGF) family members, FGF21 has been extensively investigated for its potential as a drug candidate to combat metabolic diseases. In the present study, recombinant human FGF21 (rhFGF21) was modified with polyethylene glycol (PEGylation) in order to increase its in vivo biostabilities and therapeutic potency. At N-terminal residue rhFGF21 was site-selectively PEGylated with mPEG20 kDa-butyraldehyde. The PEGylated rhFGF21 was purified to near homogeneity by Q Sepharose anion-exchange chromatography. The general structural and biochemical features as well as anti-diabetic effects of PEGylated rhFGF21 in a type 2 diabetic rat model were evaluated. By N-terminal sequencing and MALDI-TOF mass spectrometry, we confirmed that PEG molecule was conjugated only to the N-terminus of rhFGF21. The mono-PEGylated rhFGF21 retained the secondary structure, consistent with the native rhFGF21, but its biostabilities, including the resistance to physiological temperature and trypsinization, were significantly enhanced. The in vivo immunogenicity of PEGylated rhFGF21 was significantly decreased, and in vivo half-life time was significantly elongated. Compared to the native form, the PEGylated rhFGF21 had a similar capacity of stimulating glucose uptake in 3T3-L1 cells in vitro, but afforded a significantly long effect on reducing blood glucose and triglyceride levels in the type 2 diabetic animals. These results suggest that the PEGylated rhFGF21 is a better and more effective anti-diabetic drug candidate than the native rhFGF21 currently available. Therefore, the PEGylated rhFGF21 may be potentially applied in clinics to improve the metabolic syndrome for type 2 diabetic patients.


Anti-beta2GPI-antibody-induced endothelial cell gene expression profiling reveals induction of novel pro-inflammatory genes potentially involved in primary antiphospholipid syndrome.
To determine the effects of primary antiphospholipid syndrome (PAPS)-derived anti-beta(2)GPI antibodies on gene expression in human umbilical vein endothelial cells (HUVEC) by gene profiling using microarrays. Anti-beta(2)GPI antibodies purified from sera of patients with PAPS or control IgG isolated from normal subjects were incubated with HUVEC for 4 h before isolation of RNA and processing for hybridisation to Affymetrix Human Genome U133A-2.0 arrays. Data were analysed using a combination of the MAS 5.0 (Affymetrix) and GeneSpring (Agilent) software programmes. For selected genes microarray data were confirmed by real-time PCR analysis or at the protein level by ELISA. A total of 101 genes were found to be upregulated and 14 genes were downregulated twofold or more in response to anti-beta(2)GPI antibodies. A number of novel genes not previously associated with APS were induced, including chemokines CCL20, CXCL3, CX3CL1, CXCL5, CXCL2 and CXCL1, the receptors Tenascin C, OLR1, IL-18 receptor 1, and growth factors CSF2, CSF3 IL-6, IL1beta and FGF18. The majority of downregulated genes were transcription factors/signalling molecules including ID2. Quantitative real-time RT-PCR analysis confirmed the microarray results for selected genes (CSF3, CX3CL1, FGF18, ID2, SOD2, Tenascin C). This study reveals a complex gene expression response in HUVEC to anti-beta(2)GPI antibodies with multiple chemokines, pro-inflammatory cytokines, pro-thrombotic and pro-adhesive genes regulated by these antibodies in vitro. Some of these newly identified anti-beta(2)GPI antibody-regulated genes could contribute to the vasculopathy associated with this disease.


Analysis of common bean (Phaseolus vulgaris L., genotype BAT93) calmodulin cDNA using computational tools.
Common bean (Phaseolus vulgaris L.) is an important part of the human diet and serves as a source of natural products. Identification and understanding of genes in P. vulgaris is important for its improvement. Characterization of expressed sequence tags (ESTs) is one of the approaches in understanding the expressed genes. For the understanding of genes expression in P. vulgaris pod-tissue, research work of ESTs generation was initiated by constructing cDNA libraries using 5-day and 20-day old bean-pod-tissues. Altogether, 5972 cDNA clones were isolated to have ESTs. While processing ESTs, we found a transcript for calmodulin (CaM) gene. It is an important gene that encodes for a calcium-binding protein and known to express in all eukaryotic cells. Hence, this study was undertaken to analyse and annotate it. The objective of this study was to analyze and annotate P. vulgaris CaM (PvCaM) gene cDNA and its deduced protein (amino acids) sequence. Both strands of PvCaM cDNA clone were sequenced using M13 forward and reverse primer to elucidate the nucleotide sequence. The cDNA sequence and deduced protein sequence were analyzed and annotated using bioinformatics tools available online. The secondary structures and three-dimensional (3D) structure of PvCaM protein were predicted using the Phyre automatic fold recognition server. Results showed that PvCaM cDNA is 818 bp in length. The cDNA analysis results showed that it contains an open reading frame that encodes for 149 amino acid residues. The deduced protein sequence analysis results showed the presence of conserved domains required for CaM function. The predicted secondary structures and 3D structure are analogous to the Solanum tuberosum CaM. This study analyzed and annotated PvCaM cDNA and protein. However, in order to obtain a complete understanding of PvCaM protein, further study on its expression, structure and regulation is essential.


Investigating the role of human serum albumin protein pocket on the excited state dynamics of indocyanine green using shaped femtosecond laser pulses.
Differences in the excited state dynamics of molecules and photo-activated drugs either in solution or confined inside protein pockets or large biological macromolecules occur within the first few hundred femtoseconds. Shaped femtosecond laser pulses are used to probe the behavior of indocyanine green (ICG), the only Food and Drug Administration (FDA) approved near-infrared dye and photodynamic therapy agent, while free in solution and while confined inside the pocket of the human serum albumin (HSA) protein. Experimental findings indicate that the HSA pocket hinders torsional motion and thus mitigates the triplet state formation in ICG. Low frequency vibrational motion of ICG is observed more clearly when it is bound to the HSA protein.


Targeting Antitumoral Proteins to Breast Cancer by Local Administration of Functional Inclusion Bodies.
Two structurally and functionally unrelated proteins, namely Omomyc and p31, are engineered as CD44-targeted inclusion bodies produced in recombinant bacteria. In this unusual particulate form, both types of protein materials selectively penetrate and kill CD44+ tumor cells in culture, and upon local administration, promote destruction of tumoral tissue in orthotropic mouse models of human breast cancer. These findings support the concept of bacterial inclusion bodies as versatile protein materials suitable for application in chronic diseases that, like cancer, can benefit from a local slow release of therapeutic proteins.


Pharmacoepidemiologic Evaluation of Birth Defects from Health-Related Postings in Social Media During Pregnancy.
Adverse effects of medications taken during pregnancy are traditionally studied through post-marketing pregnancy registries, which have limitations. Social media data may be an alternative data source for pregnancy surveillance studies. The objective of this study was to assess the feasibility of using social media data as an alternative source for pregnancy surveillance for regulatory decision making. We created an automated method to identify Twitter accounts of pregnant women. We identified 196 pregnant women with a mention of a birth defect in relation to their baby and 196 without a mention of a birth defect in relation to their baby. We extracted information on pregnancy and maternal demographics, medication intake and timing, and birth defects. Although often incomplete, we extracted data for the majority of the pregnancies. Among women that reported birth defects, 35% reported taking one or more medications during pregnancy compared with 17% of controls. After accounting for age, race, and place of residence, a higher medication intake was observed in women who reported birth defects. The rate of birth defects in the pregnancy cohort was lower (0.44%) compared with the rate in the general population (3%). Twitter data capture information on medication intake and birth defects; however, the information obtained cannot replace pregnancy registries at this time. Development of improved methods to automatically extract and annotate social media data may increase their value to support regulatory decision making regarding pregnancy outcomes in women using medications during their pregnancies.


A genetic basis for anomalous band patterns encountered during DNA STR profiling.
Since 1995 the Forensic Science Service (FSS) has carried out DNA profiling of reference samples for the UK National DNA Database and in forensic casework using two multiplex STR profiling systems. During this period, profiles with anomalous banding patterns, although comparatively rare, have been encountered regularly. The FSS has collected instances of triallelic patterns and aberrant diallelic patterns. A systematic examination of these patterns has provided insight into their underlying genetic cause. The triallelic patterns could be classified into two types based on the relative intensities of their component alleles. In the Type 1 pattern the alleles were of uneven intensity, whereas in the Type 2 pattern, all three alleles were of even intensity. Evidence is presented that the more frequent Type 1 pattern is the result of somatic mutation at a heterozygous locus, and the Type 2 pattern is the result of a localized chromosomal rearrangement at a heterozygous locus. Directly from the Type 1 pattern, it was possible to deduce the size difference between the progenitor and mutated allele. All mutational changes were found to be multiples of four nucleotides, suggesting the loss or addition of one or more tetrameric repeat units. Aberrant diallelic patterns were identified by analysts due to an unexpectedly large difference in intensity between alleles at a heterozygous locus. While some of these diallelic patterns are likely caused by the same genetic phenomena described above occurring at a homozygous locus, others are demonstrated to be caused by a mutation in the primer binding sequence, leading to a reduction in amplification efficiency of one allele. It is concluded that based on a visual inspection of a profile, it is possible to infer a likely genetic basis directly from the triallelic pattern. By contrast, the aberrant diallelic patterns can be due to any one of a number of possible genetic effects.


Comprehensive analysis of sperm DNA fragmentation by five different assays: TUNEL assay, SCSA, SCD test and alkaline and neutral Comet assay.
Sperm DNA fragmentation (SDF) is becoming an important test to assess male infertility. Several different tests are available, but no consensus has yet been reached as to which tests are most predictive of infertility. Few publications have reported a comprehensive analysis comparing these methods within the same population. The objective of this study was to analyze the differences between the five most common methodologies, to study their correlations and to establish their cut-off values, sensitivity and specificity in predicting male infertility. We found differences in SDF between fertile donors and infertile patients in TUNEL, SCSA, SCD and alkaline Comet assays, but none with the neutral Comet assay. The alkaline COMET assay was the best in predicting male infertility followed by TUNEL, SCD and SCSA, whereas the neutral COMET assay had no predictive power. For our patient population, threshold values for infertility were 20.05% for TUNEL assay, 18.90% for SCSA, 22.75% for the SCD test, 45.37% for alkaline Comet and 34.37% for neutral Comet. This work establishes in a comprehensive study that the all techniques except neutral Comet are useful to distinguish fertile and infertile men.


Regulation of expression and activity of selenoenzymes by different forms and concentrations of selenium in primary cultured chicken hepatocytes.
The expression and activity of selenoenzymes are regulated by Se. In the present study, the effects of different forms and concentrations of Se on the regulation of glutathione peroxidase (GPx) activity and phospholipid hydroperoxide GPx (GPx4) and type I deiodinase (D1) mRNA levels in chicken hepatocytes were evaluated. Primary cultured chicken hepatocyte monolayers derived from male White Leghorn chickens (aged 30-40 d) were incubated for 24 h with 0 (control), 0.5, 1, 1.5, 2, 3, 4 or 5 μmol/l of Se supplied as dl-selenomethionine (Se-Met), κ-selenocarrageenan (Se-Car) or sodium selenite (Na2SeO3). Compared with the control, Se significantly increased GPx activity in all the hepatocytes, but the activity was not increased in the hepatocytes treated with 5 μmol/l of Na2SeO3, with maximal effects being observed at 2 μmol/l of Se-Met or Se-Car and at 1.5 μmol/l of Na2SeO3, respectively. Significant decreases in GPx4 mRNA levels were observed in all the hepatocytes treated with Se (v. control). The D1 mRNA levels were significantly increased in all the groups treated with Se (v. control), with maximal effects being observed at 1.5 μmol/l of Se-Met and at 0.5 μmol/l of Se-Car or Na2SeO3, respectively. Se-Met at doses of 1.5-5 μmol/l had a greater effect on D1 mRNA than Se-Car and Na2SeO3 at equivalent doses. After resulting in a maximal effect, higher Se supplementation led to a dose-dependent reduction in GPx activity and D1 mRNA levels in all the hepatocytes treated with Se. These results suggest that in chicken hepatocytes, the regulations of GPx and D1 by different forms and concentrations of Se vary.


Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia.
The prognosis for adults with relapsed acute lymphoblastic leukemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukemia than does standard therapy. In this phase 3 trial, we randomly assigned adults with relapsed or refractory acute lymphoblastic leukemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete hematologic recovery) and overall survival. Of the 326 patients who underwent randomization, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval {CI}, 72.1 to 87.7] vs. 29.4% [95% CI, 21.0 to 38.8], P<0.001). Among the patients who had complete remission, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts) (78.4% vs. 28.1%, P<0.001); the duration of remission was longer in the inotuzumab ozogamicin group (median, 4.6 months [95% CI, 3.9 to 5.4] vs. 3.1 months [95% CI, 1.4 to 4.9]; hazard ratio, 0.55 [95% CI, 0.31 to 0.96]; P=0.03). In the survival analysis, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5.0 months [95% CI, 3.7 to 5.6] vs. 1.8 months [95% CI, 1.5 to 2.2]; hazard ratio, 0.45 [97.5% CI, 0.34 to 0.61]; P<0.001); the median overall survival was 7.7 months (95% CI, 6.0 to 9.2) versus 6.7 months (95% CI, 4.9 to 8.3), and the hazard ratio was 0.77 (97.5% CI, 0.58 to 1.03) (P=0.04). In the safety population, the most frequent grade 3 or higher nonhematologic adverse events with inotuzumab ozogamicin were liver-related. Veno-occlusive liver disease of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy. The rate of complete remission was higher with inotuzumab ozogamicin than with standard therapy, and a higher percentage of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease. Both progression-free and overall survival were longer with inotuzumab ozogamicin. Veno-occlusive liver disease was a major adverse event associated with inotuzumab ozogamicin. (Funded by Pfizer; INO-VATE ALL ClinicalTrials.gov number, NCT01564784.).


Tissue-specific transcription start site usage in the leader exons of the rat insulin-like growth factor-I gene: evidence for differential regulation in the developing kidney.
The production of insulin-like growth factor-I (IGF-I) in extrahepatic tissues supports both autocrine and paracrine functions and is regulated differently from that in liver, which supports endocrine function. In rat liver, transcription initiation primarily occurs at four distinct, widely separated sites in exon 1 of the IGF-I gene, whereas in exon 2, transcription initiation occurs at a cluster of sites. To understand the molecular basis for tissue-specific regulation of IGF-I gene expression, we have mapped transcription start site usage in the following extrahepatic tissues: testes, lung, kidney, heart, brain, muscle, and stomach, with liver serving as a control. In adult rats, kidney and brain exhibited a pattern of exon 1 transcription similar to that seen in liver, i.e. roughly equivalent use of start sites 2 and 3. In contrast, testes and lung preferentially used start site 3, while stomach, heart, and muscle predominantly used start site 3. Start sites 1 and 4 were used in all tissues at extremely low levels. In those tissues studied in which exon 2 transcripts are expressed (testes, lung, stomach, and kidney), the pattern of exon 2 transcription initiation was identical to that in adult rat liver. During postnatal development, the use of all transcription start sites in exons 1 and 2 was coordinate in lung and stomach. Selection of transcription start sites in the kidney, on the other hand, was subject to regulation during postnatal development. Specifically, within exon 1, start site 3 was expressed constitutively throughout peri- and postnatal development. In contrast, the usage of start site 2 was not detected at late fetal or early postnatal stages, but appeared and rapidly increased only at the stage of weaning. Exon 2 transcripts in kidney also did not appear until the postnatal period. These data suggest tissue-specific and developmentally regulated transcription factors regulating IGF-I promoter activity or, alternatively, tissue-specific and developmental stage-dependent differences in the stability of IGF-I mRNAs resulting from the use of different transcription start sites. These different mRNAs may be of significance in the differential regulation of IGF-I production for autocrine or paracrine function.


Improved quantification of important beer quality parameters based on nonlinear calibration methods applied to FT-MIR spectra.
During the production process of beer, it is of utmost importance to guarantee a high consistency of the beer quality. For instance, the bitterness is an essential quality parameter which has to be controlled within the specifications at the beginning of the production process in the unfermented beer (wort) as well as in final products such as beer and beer mix beverages. Nowadays, analytical techniques for quality control in beer production are mainly based on manual supervision, i.e., samples are taken from the process and analyzed in the laboratory. This typically requires significant lab technicians efforts for only a small fraction of samples to be analyzed, which leads to significant costs for beer breweries and companies. Fourier transform mid-infrared (FT-MIR) spectroscopy was used in combination with nonlinear multivariate calibration techniques to overcome (i) the time consuming off-line analyses in beer production and (ii) already known limitations of standard linear chemometric methods, like partial least squares (PLS), for important quality parameters Speers et al. (J I Brewing. 2003;109(3):229-235), Zhang et al. (J I Brewing. 2012;118(4):361-367) such as bitterness, citric acid, total acids, free amino nitrogen, final attenuation, or foam stability. The calibration models are established with enhanced nonlinear techniques based (i) on a new piece-wise linear version of PLS by employing fuzzy rules for local partitioning the latent variable space and (ii) on extensions of support vector regression variants (𝜖-PLSSVR and ν-PLSSVR), for overcoming high computation times in high-dimensional problems and time-intensive and inappropriate settings of the kernel parameters. Furthermore, we introduce a new model selection scheme based on bagged ensembles in order to improve robustness and thus predictive quality of the final models. The approaches are tested on real-world calibration data sets for wort and beer mix beverages, and successfully compared to linear methods, showing a clear out-performance in most cases and being able to meet the model quality requirements defined by the experts at the beer company. Figure Workflow for calibration of non-Linear model ensembles from FT-MIR spectra in beer production .


Nicotine and nonnicotine factors in cigarette addiction.
A great deal of research supports the role of nicotine in cigarette addiction. However, the effectiveness of nicotine replacement therapy (NRT) as a smoking cessation treatment has fallen short of initial hopes. A key reason may be that NRT does not address nonnicotine components of smoking reinforcement. These include constituents that provide reinforcing sensory stimulation, components that minimize excessive irritation from inhaled nicotine and other pharmacologically active compounds in cigarette smoke. Studies using various paradigms to dissociate nicotine from other components of smoking are summarized. Nonnicotine components provide many rewarding effects, often surpassing the direct effects of nicotine. Substitutes for the sensory effects of smoking may be effective in relieving craving for cigarettes and in facilitating smoking cessation. Moreover, techniques for devaluing smoking-related cues may decrease craving and enhance subsequent abstinence. Promising approaches for devaluing smoke cues include extinction-based treatments employing denicotinized cigarettes and the use of nicotinic agonist and/or antagonist treatment during the weeks leading up to a quit attempt. Recent studies suggest that incorporating these approaches into a treatment program may significantly increase smoking abstinence rates. Preliminary findings also suggest that replacement of the effects of monoamine oxidase inhibitors contained in cigarette smoke may enhance quit rates. While current NRT methods have been the mainstay of smoking cessation treatment and will likely continue to serve a useful role, the next stage of progress will likely entail the development of tools designed with recognition of the importance of nonnicotine components of cigarette smoking.


Metabolic flexibility and obesity in children and youth.
The concept of metabolic flexibility describes the ability of skeletal muscle to switch between the oxidation of lipid as a fuel during fasting periods to the oxidation of carbohydrate during insulin stimulated period. Alterations in energy metabolism in adults with obesity, insulin resistance and/or type 2 diabetes induce a state of impaired metabolic flexibility, or metabolic inflexibility. Despite the increase in the prevalence of type 2 diabetes in obese children and youth, less is known about the factors involved in the development of metabolic inflexibility in the paediatric population. Metabolic flexibility is conditioned by nutrient partitioning in response to feeding, substrate mobilization and delivery to skeletal muscle during fasting or exercising condition, and skeletal muscle oxidative capacity. Our aim in this review was to identify among these factors those making obese children at risk of metabolic inflexibility. The development of ectopic rather than peripheral fat storage appears to be a factor strongly linked with a reduced metabolic flexibility. Tissue growth and maturation are determinants of impaired energy metabolism later in life but also as a promising way to reverse metabolic inflexibility given the plasticity of many tissues in youth. Finally, we have attempted to identify perspectives for future investigations of metabolic flexibility in obese children that will improve our understanding of the genesis of metabolic diseases associated with obesity.


Structure of dihydroorotase from Bacillus anthracis at 2.6 Å resolution.
Dihydroorotase (EC 22.214.171.124) catalyzes the reversible cyclization of N-carbamoyl-L-aspartate to L-dihydroorotate in the third step of the pyrimidine-biosynthesis pathway in Bacillus anthracis. A comparison is made between the structures of dihydroorotase from four different organisms, including B. anthracis dihydroorotase, and reveals substantial variations in the active site, dimer interface and overall tertiary structure. These differences demonstrate the utility of exploring multiple structures of a molecular target as expressed from different organisms and how these differences can be exploited for structure-based drug discovery.


Radiological interpretation 2020: toward quantitative image assessment.
The interpretation of medical images by radiologists is primarily and fundamentally a subjective activity, but there are a number of clinical applications such as tumor imaging where quantitative imaging (QI) metrics (such as tumor growth rate) would be valuable to the patient's care. It is predicted that the subjective interpretive environment of the past will, over the next decade, evolve toward the increased use of quantitative metrics for evaluating patient health from images. The increasing sophistication and resolution of modern tomographic scanners promote the development of meaningful quantitative end points, determined from images which are in turn produced using well-controlled imaging protocols. For the QI environment to expand, medical physicists, physicians, other researchers and equipment vendors need to work collaboratively to develop the quantitative protocols for imaging, scanner calibrations, and robust analytical software that will lead to the routine inclusion of quantitative parameters in the diagnosis and therapeutic assessment of human health. Most importantly, quantitative metrics need to be developed which have genuine impact on patient diagnosis and welfare, and only then will QI techniques become integrated into the clinical environment.


Research methods workshop for health professionals in Sierra Leone: an international collaborative project.
In 1979 a research methods seminar for health professionals in Sierra Leone was conducted as part of an international medical education collaborative project between Sierra Leone, Canada, the United Kingdom and the European Economic Community. The aim of the seminar was to promote research and inquiry into national health problems. Planning and administration was conducted by Sierra Leone with Canada providing teaching materials and four tutors. Twenty-seven participants attended the seminar. Participants prepared research protocols prior to the seminar which they developed and refined during the 7 days of the workshop. Using a problem-based method Sierra Leonean health problems were used as the focus to teach epidemiological and biostatistical methods. The seminar was evaluated on the basis of a number of parameters. There was 89% attendance at the nineteen sessions. Twenty-one of the twenty-seven participants presented protocols at the final evaluation session. Self-evaluation of protocols showed improvement in most aspects but particularly in research design, methods of data gathering, analysis and ethical aspects. An opinion survey of participants showed the seminar to be viewed positively. Twelve months later six participants had submitted their protocols for funding of whom four were successful. A further seminar has been conducted in which Sierra Leoneans participated as co-tutors. This seminar format has been presented as an effective means of providing professional assistance from one country to another.


Factors affecting mode of delivery in a nullipara at term with singleton pregnancy and vertex presentation (NTSV).
To analyse the factors associated with Caesarean Section (CS) of Nulliparous, Term and Singleton pregnancies with Vertex presentation (NTSV) at a tertiary care hospital. In this unmatched retrospective case-control study, 212 NTSV patients were identified through computerized medical record systems; the data was collected through predesigned Performa by reviewing medical record charts. One hundred six CS and spontaneous vaginal deliveries (SVD) were taken as cases and controls. The mean maternal age of cases (CS) was 26.64 (SD: 3.9) and of controls (SVD) was 26.7(SD: 3.9) years, whereas mean gestational age was 38.66±1.12 and 38.57±0.9 weeks for cases and controls respectively. Ninety per cent of women in the study group were delivered within 10 hours of active labour. Babies that weighed ≤3kg were 45% and >3kg were 55%. The possibility of being high risk was twice more among those delivered by CS. However, it was not statistically significant (p value 0.077). Labour was induced in 38% patients. The Odds of Induction of Labour (IOL) were two times more and delivering at night was three times more amongst CS. The likelihood of labour exceeding 10 hours was four times (81%) if the patient had a CS. Moreover 48% of the babies weighing >3kg were delivered through CS. Maternal age, high risk pregnancies, gender of baby and epidural analgesia were not statistically significant predictors of mode of delivery (MOD) in this study. Induction of Labour, night time delivery, prolonged labour and birth weight <3kg were found to be associated with the increased CS rate among NTSV. Therefore further research is required in order to address these factors and to reduce the increasing Caesarean Section.


Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice.
Point mutations in Cu, Zn-superoxide dismutase (SOD1) cause a familial form of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Aggregates of mutant SOD1 proteins are observed in histopathology and are invoked in several proposed mechanisms for motor neuronal death; however, the significant stability and activity of the mature mutant proteins are not readily explained in such models. Recent biochemical studies suggest that it is the immature disulfide-reduced forms of the familial ALS mutant SOD1 proteins that play a critical role; these forms tend to misfold, oligomerize, and readily undergo incorrect disulfide formation upon mild oxidative stress in vitro. Here we provide physiological support for this mechanism of aggregate formation and show that a significant fraction of the insoluble SOD1 aggregates in spinal cord of the ALS-model transgenic mice contain multimers cross-linked via intermolecular disulfide bonds. These insoluble disulfide-linked SOD1 multimers are found only in the spinal cord of symptomatic transgenic animals, are not observed in unafflicted tissue such as brain cortex and liver, and can incorporate WT SOD1 protein. The findings provide a biochemical basis for a pathological hallmark of this disease; namely, incorrect disulfide cross-linking of the immature, misfolded mutant proteins leads to insoluble aggregates.


Modulation of the mechanism of apoptosis in cancer cell lines by treatment with silica-based nanostructured materials functionalized with different metallodrugs.
The mesoporous silica-based material SBA-15 (Santa Barbara Amorphous-15) has been modified with the aminodiol ligand 3-[bis(2-hydroxyethyl)amino]propyltriethoxysilane (PADOH) to give the corresponding material SBA-PADOH. Subsequent functionalization with a diorganotin(iv) compound, SnPh2Cl2 (1), and with two titanocene derivatives, TiCp2Cl2 ([Ti(η5-C5H5)2Cl2] (2)) and TiCpCpPhNfCl2 ([Ti(η5-C5H5)(η5-C5H4CHPhNf)Cl2] (3) (Ph = C6H5; Nf = C10H7)), gave the materials SBA-PADO-SnPh2 (M1), SBA-PADO-TiCp2 (M2) and SBA-PADO-TiCpCp* (M3), respectively. SBA-PADOH and M1-M3 have been characterized by various techniques such as FT-IR, XRD, XRF, solid-state NMR, nitrogen adsorption-desorption isotherms, electrochemical methods, SEM and TEM, observing that the functionalization has mainly taken place inside the pores of the corresponding porous system. In addition, mechanistic aspects of the apoptosis triggered by the synthesized materials have been studied in vitro in tumour cell lines derived from three distinct types of cancer in order to elucidate their growth inhibition and interference with the expression of tumour necrosis factor alfa (TNF-α) and the first apoptosis signal receptor (Fas or tumour necrosis factor receptor 6). It was observed that the antiproliferative and proapoptotic capacity of the materials depends on their functionalization with the different cytotoxic prodrugs (organotin or titanocene derivatives). The study shows that M1-M3 influence the metabolic activity of the tumour cells and modulate the apoptotic pathways by different mechanisms, according to the active compound inside the material.


Mathematical Models of Localized Muscle Fatigue: Sensitivity Analysis and Assessment of Two Occupationally-Relevant Models.
Muscle fatigue models (MFM) have broad potential application if they can accurately predict muscle capacity and/or endurance time during the execution of diverse tasks. As an initial step toward facilitating improved MFMs, we assessed the sensitivity of selected existing models to their inherent parameters, specifically that model the fatigue and recovery processes, and the accuracy of model predictions. These evaluations were completed for both prolonged and intermittent isometric contractions, and were based on model predictions of endurance times. Based on a recent review of the literature, four MFMs were initially chosen, from which a preliminary assessment led to two of these being considered for more comprehensive evaluation. Both models had a higher sensitivity to their fatigue parameter. Predictions of both models were also more sensitive to the alteration of their parameters in conditions involving lower to moderate levels of effort, though such conditions may be of most practical, contemporary interest or relevance. Although both models yielded accurate predictions of endurance times during prolonged contractions, their predictive ability was inferior for more complex (intermittent) conditions. When optimizing model parameters for different loading conditions, the recovery parameter showed considerably larger variability, which might be related to the inability of these MFMs in simulating the recovery process under different loading conditions. It is argued that such models may benefit in future work from improving their representation of recovery process, particularly how this process differs across loading conditions.


Carcinoembryonic Antigen (CEA) and Hepatic Metastasis in Colorectal Cancer: Update on Biomarker for Clinical and Biotechnological Approaches.
Carcinoembryonic Antigen (CEA) is a recommended prognostic marker in Colorectal Cancer (CRC) for tumor diagnosis and monitoring response to therapy. High CEA levels are specifically associated with CRC progression and increased levels of the marker are expected to fall following surgical treatment. Due to its role in CRC, CEA has also been explored as a target for cancer therapy and diagnosis approaches. The goal of this work is to highlight the role of CEA in CRC progression and liver metastasis as well as its potential as a biomarker for clinical and biotechnological approaches. A literature search of electronic medical and patent databases Pubmed, Scopus, and Science Direct, Google patents, Esp@cenet and United States Patent and Trademark Office (USPTO), was performed. Information was collected in recent publications, including 81 articles besides 13 patents related to different CEA targeting biotechnological approaches for CRC therapy and diagnosis. CEA enhances CRC metastatic potential through many ways. CEA protects metastatic cells from death, changes the microenvironment of sinusoids, promoting the expression of adhesion molecule and malignant cell survival, besides being considered a proangiogenic molecule. Furthermore CEA has also been evaluated as a target in drug delivery systems, photodynamic therapy, radioimmunotherapy, cancer imaging and nanotechnological devices, leading to many patents concerning to development of anti-CEA antibodies or their fragments with potential to target colorectal cancer and liver metastasis cells. CEA is already clinically used to monitor CRC patients, and it is a very promising targeting biomarker for multiple biotechnological applications. As far as we know this is the first report on CEA that addresses patents database.


The effects of L-theanine on alpha-band oscillatory brain activity during a visuo-spatial attention task.
Background/Objectives Ingestion of the non-proteinic amino acid L-theanine (gamma-glutamylethylamide) has been shown to influence oscillatory brain activity in the alpha band (8-14 Hz) in humans during resting electroencephalographic (EEG) recordings and also during cognitive task performance. We have previously shown that ingestion of a 250-mg dose of L-theanine significantly reduced tonic (background) alpha power during a demanding intersensory (auditory-visual) attentional cueing task. Further, cue-related phasic changes in alpha power, indexing the shorter-term anticipatory biasing of attention between modalities, were stronger on L-theanine compared to placebo. This form of cue-contingent phasic alpha activity is also known to index attentional biasing within visual space. Specifically, when a relevant location is pre-cued, anticipatory alpha power increases contralateral to the location to be ignored. Here we investigate whether the effects of L-theanine on tonic and phasic alpha activity, found previously during intersensory attentional deployment, occur also during a visuospatial task. Subjects/Methods 168-channel EEG data were recorded from thirteen neurologically normal individuals while engaged in a highly demanding visuo-spatial attention task. Participants underwent testing on two separate days, ingesting either a 250-mg colorless and tasteless solution of L-theanine mixed with water, or a water-based solution placebo on each day in counterbalanced order. We compared the alpha-band activity when subjects ingested L-Theanine vs. Placebo. Results We found a significant reduction in tonic alpha for the L-theanine treatment compared to placebo, which was accompanied by a shift in scalp topography, indicative of treatment-related changes in the neural generators of oscillatory alpha activity. However, L-theanine did not measurably affect cue-related anticipatory alpha effects. Conclusions This pattern of results implies that L-theanine plays a more general role in attentional processing, facilitating longer-lasting processes responsible for sustaining attention across the timeframe of a difficult task, rather than affecting specific moment-to-moment phasic deployment processes.


Adenylyl cyclase 3/adenylyl cyclase-associated protein 1 (CAP1) complex mediates the anti-migratory effect of forskolin in pancreatic cancer cells.
Pancreatic cancer is one of the most lethal human malignancies. A better understanding of the intracellular mechanism of migration and invasion is urgently needed to develop treatment that will suppress metastases and improve overall survival. Cyclic adenosine monophosphate (cyclic AMP) is a second messenger that has shown to regulate migration and invasion of pancreatic cancer cells. The rise of cyclic AMP suppressed migration and invasion of pancreatic ductal adenocarcinoma cells. Cyclic AMP is formed from cytosolic ATP by the enzyme adenylyl cyclase (AC). There are ten isoforms of ACs; nine are anchored in the plasma membrane and one is soluble. What remains unknown is the extent to which the expression of transmembrane AC isoforms is both modified in pancreatic cancer and mediates the inhibitory effect of forskolin on cell motility. Using real-time PCR analysis, ADCY3 was found to be highly expressed in pancreatic tumor tissues, resulting in a constitutive increase in cyclic AMP levels. On the other hand, ADCY2 was down-regulated. Migration, invasion, and filopodia formation in two different pancreatic adenocarcinoma cell lines, HPAC and PANC-1 deficient in AC1 or AC3, were studied. We found that AC3, upon stimulation with forskolin, enhanced cyclic AMP levels and inhibited cell migration and invasion. Unlikely to be due to a cytotoxic effect, the inhibitory effects of forskolin involved the quick formation of AC3/adenylyl cyclase-associated protein 1 (CAP1)/G-actin complex, which inhibited filopodia formation and cell motility. Using Western blotting analysis, forskolin, through AC3 activation, caused phosphorylation of CREB, but not ERK. The effect of CREB phosphorylation is likely to be associated with long-term signaling changes. © 2016 Wiley Periodicals, Inc.


Disposal of exogenous amino acids by muscle in patients with chronic renal failure.
Muscle exchange of amino acids (AAs) was evaluated by using the arteriovenous-difference technique across the leg in seven patients with chronic renal failure (CRF) and eight control subjects before and for 75 min after the ingestion of an AA mixture simulating an animal-protein meal. Total AAs increased in arterial blood much more in patients with CRF after AA ingestion than in control subjects, as a consequence of an exaggerated increase in nonessential AAs (NEAAs) (+127%). Moreover, total AAs were taken up by the leg in larger amounts than in control subjects (+71%, P < 0.0025) because of increased uptake of NEAAs (+156%, P < 0.005). Branched-chain AA uptake by the leg was, in absolute values, similar to that of control subjects; however, because of the increased uptake of total AAs, branched-chain AA uptake was only 30% of total AA extraction, compared with 46% in control subjects. Abnormalities in AA uptake by muscle paralleled those in arterial AAs. In fact the same AAs that increased abnormally in blood were taken up by the leg at higher rates than in control subjects. Variations in arterial concentrations and muscle uptake of AAs were inversely related to arterial bicarbonate concentration, suggesting a role for acid-base status in modifying both the arterial supply and muscle metabolism of AAs. Results indicate that in CRF patients the normal pattern of postprandial AA repletion is disrupted. Muscle tissue faces the increased and unbalanced postprandial supply of AAs with an augmented and unbalanced uptake. Data are consistent with an abnormal use of exogenous AAs in CRF patients, possibly induced by metabolic acidosis.


Peripherally inserted central catheter (PICC) complications during pregnancy.
Peripherally inserted central catheters (PICCs) are routinely used in women with hyperemesis gravidarum. However, little is known about the consequences of PICC insertion in these patients. Our aim was to analyze PICC-related complication rates among pregnant women. Pregnant women with PICC insertion between January 2000 and June 2006 were studied retrospectively. Infusate type, comorbid conditions, and PICC duration were characterized. Major complications, defined as need for surgical intervention, bacteremia requiring intravenous antibiotics, or thromboembolic events, were identified. Minor complications, including phlebitis, PICC malfunction, early PICC removal, infection requiring oral antibiotics, or hospitalization for PICC evaluation, were also studied. Eighty-four catheters in 66 women were eligible for study, totaling 2544 PICC days. Catheters remained in place for 1-177 days; median duration was 21.0 days. PICCs were used for intravenous fluid (IVF, 59.4%), parenteral nutrition (PN, 34.5%), and antibiotics (6%). The overall complication rate was 18.5 per 1000 PICC days (55.9% of PICCs); 22.6% were major, with bacteremia being most frequent (20.2%). A diagnosis of diabetes was the only factor that significantly predicted complications (hazard ratio, 2.71; 95% confidence interval, 1.13-6.13). PICC duration and type of infusate (PN vs IVF alone) were not associated with complications. PICC insertion in pregnant women is associated with a high complication rate, which appears to be independent of the type of infusate and occurs in the majority of women. PICCs should be used judiciously and only when clearly necessary during pregnancy. Further studies are needed to determine how to reduce PICC-related complications in this population.


Methicillin-Resistant Staphylococcus aureus: Molecular Characterization, Evolution, and Epidemiology.
Staphylococcus aureus, a major human pathogen, has a collection of virulence factors and the ability to acquire resistance to most antibiotics. This ability is further augmented by constant emergence of new clones, making S. aureus a "superbug." Clinical use of methicillin has led to the appearance of methicillin-resistant S. aureus (MRSA). The past few decades have witnessed the existence of new MRSA clones. Unlike traditional MRSA residing in hospitals, the new clones can invade community settings and infect people without predisposing risk factors. This evolution continues with the buildup of the MRSA reservoir in companion and food animals. This review focuses on imparting a better understanding of MRSA evolution and its molecular characterization and epidemiology. We first describe the origin of MRSA, with emphasis on the diverse nature of staphylococcal cassette chromosome mec (SCCmec). mecA and its new homologues (mecB, mecC, and mecD), SCCmec types (13 SCCmec types have been discovered to date), and their classification criteria are discussed. The review then describes various typing methods applied to study the molecular epidemiology and evolutionary nature of MRSA. Starting with the historical methods and continuing to the advanced whole-genome approaches, typing of collections of MRSA has shed light on the origin, spread, and evolutionary pathways of MRSA clones.


Intracellular magnesium and adipokines in umbilical cord plasma and infant birth size.
Many epidemiologic studies have disclosed that restricted fetal growth has been associated with an increased risk of insulin resistance in adulthood. We studied the relationship of intracellular magnesium [Mg2+]i in cord blood platelets to adipocytokine and birth size. The subjects were 20 infants with small for gestational age (SGA) and 45 infants with appropriate for gestational age (AGA). By using a fluorescent probe, we examined [Mg2+]i of platelets in the cord blood. Cord plasma insulin, IGF-I, ghrelin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), and leptin levels were determined with the use of ELISA. Mean [Mg2+]i was lower in the SGA than in the AGA groups (p < 0.001). Adiponectin and IGF-I were also lower in the SGA than in the AGA, whereas PAI-1 was higher in the SGA. [Mg2+]i was significantly correlated with birth weight, birth length, and adiponectin. Birth weight was also correlated with cord plasma IGF-I, adiponectin, and leptin. Quantitative insulin sensitivity check index (QUICKI) was lower in the SGA group than in the AGA group. [Mg]i and adiponectin were correlated with QUICKI in all subjects. [Mg]i, as well as leptin and IGF-I, reflect the extent of fetal growth. Decreased [Mg2+]i may be involved in the underlying processes to insulin resistance.


How unemployment scarring affects skilled young workers: evidence from a factorial survey of Swiss recruiters.
We ask how employers contribute to unemployment scarring in the recruitment process in the German-speaking part of Switzerland. By drawing on recruitment theories, we aim to better understand how recruiters assess different patterns of unemployment in a job candidate's CV and how this affects the chances of young applicants being considered for a vacancy. We argue that in contexts with tight school-work linkage and highly standardised Vocational Education and Training systems, the detrimental effect of early unemployment depends on how well the applicant's profile matches the requirements of the advertised position. To test this assumption, we surveyed Swiss recruiters who were seeking to fill positions during the time of data collection. We employed a factorial survey experiment that tested how the (un)employment trajectories in hypothetical young job applicants' CV affected their chances of being considered for a real vacancy. Our results show that unemployment decreases the perceived suitability of an applicant for a specific job, which implies there is a scarring effect of unemployment that increases with the duration of being unemployed. But we also found that these effects are moderated by how well the applicant's profile matches the job's requirements. Overall, the worse the match between applicant's profile and the job profile, the smaller are the scarring effects of unemployment. In sum, our findings contribute to the literature by revealing considerable heterogeneity in the scarring effects of unemployment. Our findings further suggest that the scarring effects of unemployment need to be studied with regard to country-specific institutional settings, the applicants' previous education and employment experiences, and the job characteristics.


Isotopomer analysis of myocardial substrate metabolism: a systems biology approach.
The increasing accessibility of mass isotopomer data via GC-MS and NMR technology has necessitated the use of a systematic and reliable method to take advantage of such data for flux analysis. Here we applied a nonlinear, optimization-based method to study substrate metabolism in cardiomyocytes using (13)C data from perfused mouse hearts. The myocardial metabolic network used in this study accounts for 257 reactions and 240 metabolites, which are further compartmentalized into extracellular space, cytosol, and mitochondrial matrix. Analysis of the perfused mouse heart showed that the steady-state ATP production rate was 16.6 +/- 2.3 micromol/min . gww, with 30% of the ATP coming from glycolysis. Of the four substrates available in the perfusate (glucose, pyruvate, lactate, and oleate), exogenous glucose forms the majority of cytosolic pyruvate. Pyruvate decaboxylation is significantly higher than carboxylation, suggesting that anaplerosis is low in the perfused heart. Exchange fluxes were predicted to be high for reversible enzymes in the citric acid cycle (CAC), but low in the glycolytic pathway. Pseudoketogenesis amounted to approximately 50% of the net ketone body uptake. Sensitivity analysis showed that the estimated flux distributions were relatively insensitive to experimental errors. The application of isotopomer data drastically improved the estimation of reaction fluxes compared to results computed with respect to reaction stoichiometry alone. Further study of 12 commonly used (13)C glucose mixtures showed that the mixtures of 20% [U-(13)C(6)] glucose, 80% [3 (13)C] glucose and 20% [U-(13)C(6)] glucose, 80% [4 (13)C] were best for resolving fluxes in the current network.


Reflective performance of Ir film in vacuum ultraviolet wavelength region.
This paper theoretically and experimentally investigates the reflective performance of Ir films in the vacuum ultraviolet wavelength region. Ir reflecting layers of different thicknesses on various substrates are calculated and fabricated by the ion-beam-sputtering technique. Their reflectance in the 115 nm to 140 nm wavelength region was measured continuously by a reflectometer located at the National Synchrotron Radiation Laboratory. The testing results show that the reflectance of Si substrates is quite sensitive to the deposited Ir layer thickness, while the reflectance on a quartz or a BK7 glass substrates is higher. The energy of the sputtering ion beam exerts a significant influence on the reflectance of the layer, and the postannealing can cause a substantial decrease in the reflectance. For normal incidence, the reflectance of an Ir film on BK7 glass can reach as high as 30%.


Evidence against association between parity and NIDDM from five population groups.
To determine whether a reported positive association between parity and the development of non-insulin-dependent diabetes mellitus (NIDDM) and impaired glucose tolerance (IGT) is reproducible in other populations. We investigated the relationship in data from population-based surveys in four Pacific and Indian Ocean island nations. Women greater than or equal to 40 yr of age at the time of the survey, excluding those in whom diabetes developed before 40 yr of age, were included in this study of Micronesians from Nauru (n = 204) and Kiribati (n = 562), Fiji Melanesians (n = 390), Fiji Indians (n = 247), and mixed-ethnic Mauritians (n = 1333). Subjects in each survey underwent a 75-g oral glucose tolerance test, and glucose tolerance status was ascertained with 1985 World Health Organization criteria. Obstetric information and family history of diabetes were determined by interview. Age and body mass index (BMI)-adjusted mean parity increased slightly with worsening glucose tolerance in only two groups, decreased in one group, and was inconsistent in the other two (none were statistically significant). We also found an inconsistent relationship between the number of full-term pregnancies and the prevalence of IGT and NIDDM, although in each population, there was a higher prevalence of NIDDM in the highest parity group (greater than or equal to 10 pregnancies) compared with the lowest parity group (1-3 pregnancies). In logistic regression analyses accounting for age, BMI, and family history of diabetes, odds ratio estimates for NIDDM and IGT associated with each pregnancy were not significantly greater than unity. The results indicate that there is little if any independent association between parity and the development of abnormal glucose tolerance in these populations.


Strategies for the production of difficult-to-express full-length eukaryotic proteins using microbial cell factories: production of human alpha-galactosidase A.
Obtaining high levels of pure proteins remains the main bottleneck of many scientific and biotechnological studies. Among all the available recombinant expression systems, Escherichia coli facilitates gene expression by its relative simplicity, inexpensive and fast cultivation, well-known genetics and the large number of tools available for its biotechnological application. However, recombinant expression in E. coli is not always a straightforward procedure and major obstacles are encountered when producing many eukaryotic proteins and especially membrane proteins, linked to missing posttranslational modifications, proteolysis and aggregation. In this context, many conventional and unconventional eukaryotic hosts are under exploration and development, but in some cases linked to complex culture media or processes. In this context, alternative bacterial systems able to overcome some of the limitations posed by E. coli keeping the simplicity of prokaryotic manipulation are currently emerging as convenient hosts for protein production. We have comparatively produced a "difficult-to-express" human protein, the lysosomal enzyme alpha-galactosidase A (hGLA) in E. coli and in the psychrophilic bacterium Pseudoalteromonas haloplanktis TAC125 cells (P. haloplanktis TAC125). While in E. coli the production of active hGLA was unreachable due to proteolytic instability and/or protein misfolding, the expression of hGLA gene in P. haloplanktis TAC125 allows obtaining active enzyme. These results are discussed in the context of emerging bacterial systems for protein production that represent appealing alternatives to the regular use of E. coli and also of more complex eukaryotic systems.


3D multi-energy deconvolution electron microscopy.
Three-dimensional (3D) characterization of nanomaterials is traditionally performed by either cross-sectional milling with a focused ion beam (FIB), or transmission electron microscope tomography. While these techniques can produce high quality reconstructions, they are destructive, or require thin samples, often suspended on support membranes. Here, we demonstrate a complementary technique allowing non-destructive investigation of the 3D structure of samples on bulk substrates. This is performed by imaging backscattered electron (BSE) emission at multiple primary beam energies - as the penetration depth of primary electrons is proportional to the beam energy, depth information can be obtained through variations in the beam acceleration. The detected signal however consists of a mixture of the penetrated layers, meaning the structure's three-dimensional geometry can only be retrieved after deconvolving the BSE emission profile from the observed BSE images. This work demonstrates this novel approach by applying a blind source separation deconvolution algorithm to multi-energy acquired BSE images. The deconvolution can thereby allow a 3D reconstruction to be produced from the acquired images of an arbitrary sample, showing qualitative agreement with the true depth structure, as verified through FIB cross-sectional imaging.


Chronic kidney disease of unknown origin is associated with environmental urbanisation in Belfast, UK.
Chronic kidney disease (CKD), a collective term for many causes of progressive renal failure, is increasing worldwide due to ageing, obesity and diabetes. However, these factors cannot explain the many environmental clusters of renal disease that are known to occur globally. This study uses data from the UK Renal Registry (UKRR) including CKD of uncertain aetiology (CKDu) to investigate environmental factors in Belfast, UK. Urbanisation has been reported to have an increasing impact on soils. Using an urban soil geochemistry database of elemental concentrations of potentially toxic elements (PTEs), we investigated the association of the standardised incidence rates (SIRs) of both CKD and CKD of uncertain aetiology (CKDu) with environmental factors (PTEs), controlling for social deprivation. A compositional data analysis approach was used through balances (a special class of log contrasts) to identify elemental balances associated with CKDu. A statistically significant relationship was observed between CKD with the social deprivation measures of employment, income and education (significance levels of 0.001, 0.01 and 0.001, respectively), which have been used as a proxy for socio-economic factors such as smoking. Using three alternative regression methods (linear, generalised linear and Tweedie models), the elemental balances of Cr/Ni and As/Mo were found to produce the largest correlation with CKDu. Geogenic and atmospheric pollution deposition, traffic and brake wear emissions have been cited as sources for these PTEs which have been linked to kidney damage. This research, thus, sheds light on the increasing global burden of CKD and, in particular, the environmental and anthropogenic factors that may be linked to CKDu, particularly environmental PTEs linked to urbanisation.


Emotions in action through the looking glass.
The paper aims at highlighting how our primary understanding of others' actions is rooted in the mirror mechanism. To this end, the anatomical architecture of the mirror neuron system for action will be outlined as well as its role in grasping goals and intentions in others' motor behaviour. One further step through the looking glass of social cognition will be referring to the ubiquitous emotional colouring of actions and considering its links with the motor domain. This will allow a clearer perspective on the mechanism underlying our abilities for emotional understanding and on cases in which these abilities are amiss, as in autistic spectrum disorders.


[Estimation and analysis of HIV incidence in the adult population in Peru: results of application of the MoT mathematical model].
To estimate HIV incidence in the adult population of Peru, 2010, and analyze its distribution based on risk behavior. The UNAIDS model was applied based on the modes of transmission (MoT). The information was obtained from the review detailed in 59 documents (1984 - 2008). National databases were also analyzed to obtain specific data. Final selection of data was validated by the technical group and a group of experts. After consultation with experts, values were corrected and an uncertainty analysis was conducted. The model was adjusted to 2009 national prevalence (0.45%). Incidence estimated for 2010 was 0.03%, (4346 new infections). 84% of new infections concentrate on higher risk groups: men who have sex with men (55%) and people who have casual sex with heterosexuals (6.2%). The remaining 16% corresponds to low-risk heterosexual population. Heterosexual transmission accounts for 43% of new cases, 18% of which corresponds to female partners of high risk individuals. Only 2.2% of cases is related to female sexual work and 1.0% to injection drug users. The model provides an estimation of the incidence and its distribution among risk groups according to the mode of transmission, consistent with the HIV case reporting. The model creates scenarios to help decision making and policy formulation, as well as surveillance and planning of prevention and control.


IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas.
Patients with metastatic or recurrent and refractory sarcomas have a dismal prognosis. Therefore, new targeted therapies are urgently needed. This study was designed to evaluate chimeric antigen receptor (CAR) T cells targeting the type I insulin-like growth factor receptor (IGF1R) or tyrosine kinase-like orphan receptor 1 (ROR1) molecules for their therapeutic potential against sarcomas. Here, we report that IGF1R (15/15) and ROR1 (11/15) were highly expressed in sarcoma cell lines including Ewing sarcoma, osteosarcoma, alveolar or embryonal rhabdomyosarcoma, and fibrosarcoma. IGF1R and ROR1 CAR T cells derived from eight healthy donors using the Sleeping Beauty (SB) transposon system were cytotoxic against sarcoma cells and produced high levels of IFN-γ, TNF-α and IL-13 in an antigen-specific manner. IGF1R and ROR1 CAR T cells generated from three sarcoma patients released significant amounts of IFN-γ in response to sarcoma stimulation. The adoptive transfer of IGF1R and ROR1 CAR T cells derived from a sarcoma patient significantly reduced tumor growth in pre-established, systemically disseminated and localized osteosarcoma xenograft models in NSG mice. Infusion of IGF1R and ROR1 CAR T cells also prolonged animal survival in a localized sarcoma model using NOD/scid mice. Our data indicate that both IGF1R and ROR1 can be effectively targeted by SB modified CAR T cells and that such CAR T cells may be useful in the treatment of high risk sarcoma patients.


The association between NOTCH3 expression and the clinical outcome in the urothelial bladder cancer patients.
Disrupted NOTCH activity is a driving event in urothelial bladder cancer (UBC). After activation by hypoxia, the NOTCH3 receptor participates in tumor cell proliferation, acquisition of the epithelial-mesenchymal transition phenotype, and angiogenesis. The aim was to analyze the association of NOTCH3 expression with histopathological and clinical parameters, and to determine its predictive impact on the clinical outcome in UBC patients. The present research included 614 UBC samples incorporated in paraffin tissue microarrays, evaluated by immunohistochemistry for NOTCH3 expression. The accrual period was four years, while the follow-up period was two years. The membranous expression was semi-quantified (0-3), and the mean degree was 1.81±0.94. Criteria for semi-quantification the NOTCH3 expression were the intensity of the staining and the percentage of positive cells. The samples with negative (0) and weak (1) NOTCH3 immunohistochemical (IHC) score were considered negative, while the samples that showed moderate (2) and strong (3) expression were considered positive. Higher degree of positivity was associated with higher risk of cancer-specific mortality (p<0.001). Independent predictors for cancer-specific mortality were NOTCH3 expression and high stage (p<0.001). NOTCH3 expression was not a statistically significant predictor of recurrence-free survival (p=0.816). This study indicated that NOTCH3 is a predictor of poor outcome, suggesting that the NOTCH3 could be potentially reliable IHC marker for selecting the UBC patients that would require more intensive follow-up, especially if they diagnosed in higher stage, with divergent differentiation in pathological report, and without recurrences which would lead them to more frequent medical assessments.


Integration of phenotyping and genetic platforms for a better understanding of wheat performance under drought.
Identifying markers for physiological traits of proven value in breeding, especially ones that are consistent across environments with different patterns of stress, strengthens the toolkit to increase confidence in the value and delivery from physiological breeding. To identify markers relevant to drought adaptation, this review will highlight the importance of development and implementation of robust and repeatable phenotyping that is relevant to the different target drought types, and practical examples of managed environment facilities in Australia and Mexico are given. These facilities can be used as models to: (i) improve reliability and consistency of environments and genetic responses to the environment at a global scale; (ii) improve the capacity to deliver quantitative trait loci (QTLs) as user-friendly markers for enriching populations; and (iii) illustrate the use of populations with a narrow range of variation for phenology allowing the identification of QTLs for drought-adaptive traits. However, the importance of further optimizing phenology and plant height at a global scale is highlighted. Finally, the impact of physiological trait-based crossing is demonstrated and supports the need for urgent development of robust genetic markers.


Injectable versus topical anesthesia for cataract surgery: patient perceptions of pain and side effects. The Study of Medical Testing for Cataract Surgery study team.
To compare patient reports of intraoperative pain and postoperative side effects by different anesthesia strategies for cataract surgery. Prospective cohort study. Men and women 50 years of age and older undergoing 19,250 cataract surgeries at nine centers in the United States and Canada from June 1995 through June 1997. Topical anesthesia or anesthesia with injection, with or without sedatives, opioid analgesia, hypnotics, and diphenhydramine (Benadryl). Patient ratings of intraoperative pain, satisfaction with pain management, and early postoperative side effects (drowsiness, nausea, vomiting, or a combination thereof). Twenty-six percent of surgeries were performed using topical anesthesia alone, and the remainder were performed with peribulbar, retrobulbar, or facial nerve block, or a combination thereof. Local anesthesia by injection with sedatives and diphenhydramine resulted in the lowest reporting of any intraoperative pain (1.3%), with postoperative drowsiness (9.6%) and nausea, vomiting, or both (1.5%) comparable with those administered topical anesthesia alone. Among those receiving topical anesthesia, use of sedatives and opioids reduced reports of any pain during surgery by 56% (95% confidence interval [CI], 34%, 70%), but increased nausea and vomiting (odds ratio, 2.27; 95% CI, 1.26, 4.09) compared with those administered topical anesthesia alone, after adjusting for age, gender, race, American Society of Anesthesiologists risk class, self-reported health status, and duration of surgery. Among those receiving local injections, use of opioids reduced reports of any pain among those receiving sedatives by 37% (95% CI, 15%, 54%), but did not increase postoperative side effects. The use of diphenhydramine among those receiving sedatives decreased reports of any pain by 59% (95% CI, 33%, 75%) and also reduced drowsiness and nausea and vomiting by 57% (95% CI, 48%, 65%) and by 60% (95% CI, 36%, 75%), respectively. Use of hypnotics with sedatives was associated with increased reports of any pain during surgery and increased nausea and vomiting after surgery. Patient reports of any pain during cataract surgery (5%) and postoperative side effects (16% drowsiness and 4% nausea and vomiting) were low, but varied by anesthesia strategy. Patient perceptions of pain and side effects can be helpful in guiding the appropriate choice of anesthesia strategy.


Mitochondrial Molecular Abnormalities Revealed by Proteomic Analysis of Hippocampal Organelles of Mice Triple Transgenic for Alzheimer Disease.
Mitochondrial dysfunction is implicated in the pathogenesis of Alzheimer's disease (AD). However, the precise mitochondrial molecular deficits in AD remain poorly understood. Mitochondrial and nuclear proteomic analysis in mature male triple transgenic AD mice (PS1M146V/APPSwe/TauP301L) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with MALDI-TOF-MS/MS, bio-informatics analysis and immunofluorescent staining were performed in this study. In addition to impaired spatial memory impairment and intracellular accumulation of amyloid 1-42 (Aβ1-42) in the 3xTg-AD mice, a well-accepted mouse model of the human disease, we also found significantly increased DNA oxidative damage in entorhinal cortex, hippocampal CA1, CA3 and dental gyrus (DG), as evidenced by the positive staining of 8-hydroxyguanosine, a biomarker of mild cognitive impairment early in AD. We identified significant differences in 27 hippocampal mitochondrial proteins (11 increased and 16 decreased), and 37 hippocampal nuclear proteins (12 increased and 25 decreased) in 3xTg-AD mice compared with the wild-type (WT) mice. Differentially expressed mitochondrial and nuclear proteins were mainly involved in energy metabolism (>55%), synapses, DNA damage, apoptosis and oxidative stress. Two proteins were differentially expressed in both hippocampal mitochondria and nuclei, namely electron transport chain (ETC)-related protein ATP synthase subunit d (ATP5H) was significantly decreased, and apoptosis-related dynamin-1 (DYN1), a pre-synaptic and mitochondrial division-regulated protein that was significantly increased. In sum, perturbations of hippocampus mitochondrial energy metabolism-related proteins responsible for ATP generation via oxidation phosphorylation (OXPHOS), especially nuclear-encoded OXPHOS proteins, correlated with the amyloid-associated cognitive deficits of this murine AD model. The molecular changes in respiratory chain-related proteins and DYN1 may represent novel biomarkers of AD.


The regulation of malaria parasitaemia: parameter estimates for a population model.
Classical studies of non-immune individuals infected with Plasmodium falciparum reveal that the infection may be regulated for long periods at a relatively stable parasite density, despite the enormous growth potential of a parasite that continually replicates within host erythrocytes. This suggests that the parasite population may be controlled by density-dependent mechanisms, and in theory the most obvious of these is competition between parasites for host erythrocytes. Here we evaluate the role of this mechanism in the regulation of parasitaemia, by modelling the basic population interaction between parasites and erythrocytes in a form that allows all the essential parameters to be estimated from clinical data. Our results show that competition cannot account for the total regulation of P. falciparum, but when combined with immune mechanisms it may play a more important role than is generally supposed. Further analysis of the model indicates that in the long term, parasite replication at low parasite densities can contribute significantly to the high degree of anaemia observed in natural infection, a conclusion which is not obvious from simple clinical observation.


Systematic review of time studies evaluating physicians in the hospital setting.
Time studies, first developed in the late 19th century, are now being used to evaluate and improve worker efficiency in the hospital setting. This is the first review of hospital time study literature of which we are aware. We performed a systematic review of the literature to better understand the available time study literature describing the activities of hospital physicians. We searched MEDLINE, EMBASE, EMBASE Classic, PsycINFO, Cochrane Library, CINAHL, and Web of Science. We also manually reviewed the reference lists of retrieved articles and consulted experts in the field to identify additional articles for review. We selected studies that used time-motion or work-sampling performed via direct observation, included physicians, medical residents, or interns in their study population, and were performed on an inpatient hospital ward. We abstracted data on subject population, study site, collection tools, and percentage of time spent on key categories of activity. Our search produced 11 time-motion and 2 work-sampling studies that met our criteria. These studies focused primarily on academic hospitals (92%) and the activities of physicians in training (69%). Other results varied widely. A lack of methodological standardization and dissimilar activity categorizations inhibited our efforts to summarize detailed findings across studies. However, we consistently found that activities indirectly related to a patient's care took more of hospital physicians' time than direct interaction with hospitalized patients. Time studies, when properly performed, have a great deal to offer in helping us understand and reengineer hospital care.


Relations of Postload and Fasting Glucose With Incident Cardiovascular Disease and Mortality Late in Life: The Cardiovascular Health Study.
Older adults have a high prevalence of postload hyperglycemia. Postload glucose has shown more robust associations with cardiovascular disease (CVD) and death than fasting glucose, but data in the oldest old are sparse. Fasting and 2-hour postload glucose were measured in community-dwelling older adults, mean age 78, at the 1996-1997 follow-up visit of the Cardiovascular Health Study. We evaluated their associations with atherosclerotic CVD (ASCVD) and mortality using standard Cox regression and competing-risks analyses and assessed improvement in prediction-model discrimination with the c-statistic. Among 2,394 participants without treated diabetes and available data on glycemic measures, there were 579 ASCVD events and 1,698 deaths during median follow-up of 11.2 years. In fully adjusted models, both fasting and 2-hour glucose were associated with ASCVD (HR per SD, 1.13 [1.03-1.25] and 1.17 [1.07-1.28], respectively) and all-cause mortality (HR 1.12 [1.07-1.18] and 1.14 [1.08-1.20]). After mutual adjustment, however, the associations for fasting glucose with both outcomes were abolished, but those for postload glucose were largely unchanged. Consistent findings were observed for ASCVD in competing-risks models. In adults surviving to advanced old age, postload glucose was associated with ASCVD and mortality independently of fasting glucose, but fasting glucose was not associated with these outcomes independently of postload glucose. These findings affirm the robust association of postload glucose with ASCVD and death late in life.


Analysis of two different techniques in the treatment of knee stiffness in swing phase due to fibrous rectus femoris muscle in children.
The objective of this study was to analyze two surgical techniques in the treatment of fibrous rectus femoris muscle in children. Data from 152 patients (161 knees) from July 1991 to December 2004 were analyzed. Clinical signs were knee stiffness in swing phase, positive Ely and Ober tests, and abnormal flexion angles of the knee and hip. Patients were operated according to one of two variants: variant A, to release the proximal tendon and variant B, to release the middle shaft of the rectus femoris muscle. There were 96 women (63.2%) and 56 men (36.8%) in this study. Bilateral involvement was found in nine patients; only the left knee was affected in 34 patients (22.4%) and only the right knee in 109 patients (71.7%). All 152 patients (161 knees) developed fibrous rectus femoris muscle (RFM) after repeated intramuscular injection of antibiotic(s) into the RFM. A total of 145 knees (136 patients) were classified as severe and 16 knees (16 patients) were classified as moderate. Overall, we attained excellent results in 109 (67.7%), good results in 26 (16.1%), fair results in 14 (8.7%), and poor results in 12 knees (7.5%). There have been no complications so far. Generally, surgical treatment of knee stiffness in swing phase due to fibrous RFM according to variant B led to postoperative poor results in only 1.2% of patients, whereas variant A gave postoperative poor results in 14.5% of patients. The surgical procedure is simple and safe, and knee and hip functions, tendency for crouch gait, and anterior pelvic tilt were remarkably improved.


Superagonistic behaviour of epidermal growth factor/transforming growth factor-alpha chimaeras: correlation with receptor routing after ligand-induced internalization.
Human epidermal growth factor (EGF) and human transforming growth factor alpha (TGF-alpha) are structurally related polypeptide growth factors that exert their mitogenic activity through interaction with a common cell-surface receptor, the epidermal growth factor receptor (EGFR). The biological effect induced by these two ligands is quantitatively similar in most cases; in some test systems, however, TGF-alpha functions as a more potent form of EGF. In this study, we have compared EGF, TGF-alpha and ten previously described chimaeras of these two ligands in terms of their ability to generate a mitogenic response in cells carrying the human EGFR, and observed that three of the mutant growth factors (E3T, E4T and T3E4T) are mitogenic at concentrations 10-fold lower than that of either wild-type EGF or TGF-alpha. No difference in tyrosine kinase activity of the receptor towards an external substrate was observed after binding of the various mutants. It has been established before [Ebner and Derynck (1991) Cell Regulation 2, 599-612] that EGF and TGF-alpha differ in the processing of the receptor-ligand complex after internalization, as a result of their different pH sensitivities of receptor binding. Similar measurements on our chimaeric mutants revealed that the above superagonists show an enhanced pH dependence of binding in comparison with EGF. Furthermore, induction of receptor recycling by these superagonists is largely comparable with that induced by TGF-alpha. No superagonistic behaviour was observed on a cell-line containing an EGFR/erbB-2 chimaera which does not show ligand-induced internalization. These data show that EGF/TGFalpha chimaeras can be more active than the naturally occurring ligands, and that receptor recycling after ligand-induced internalization seems to be a prerequisite for this phenomenon.


Doping a correlated band insulator: a new route to half-metallic behavior.
We demonstrate in a simple model the surprising result that turning on an on-site Coulomb interaction U in a doped band insulator leads to the formation of a half-metallic state. In the undoped system, we show that increasing U leads to a first order transition at a finite value UAF between a paramagnetic band insulator and an antiferomagnetic Mott insulator. Upon doping, the system exhibits half-metallic ferrimagnetism over a wide range of doping and interaction strengths on either side of UAF. Our results, based on dynamical mean field theory, suggest a new route to half metallicity, and will hopefully motivate searches for new materials for spintronics.


Straight From the Plastome: Molecular Phylogeny and Morphological Evolution of Fargesia (Bambusoideae: Poaceae).
Fargesia is ecologically and economically important in mountainous forests. Many Fargesia species are also important sources of food for some endangered animals such as the giant panda. Recent molecular phylogenetic analyses have revealed Fargesia as a polyphyletic group despite some unclear lineage affinities. In the present study, we reconstructed the phylogeny of Fargesia and its allies, including Thamnocalamus, Arundinaria (incl. Bashania), Yushania, Indocalamus, Ampelocalamus and Phyllostachys, from a plastome sequence matrix that contained 20 Fargesia and five Yushania species as ingroups, 16 species from nine other bamboo genera plus Oryza sativa and Zea mays as outgroups. Fargesia and its allies were broken into eight clades. Several Fargesia species were clustered into the Thamnocalamus clade and the Drepanostachyum + Himalayacalamus clade that rendered the polyphyly of Fargesia. The remaining six clades, including the Fargesia spathe clade, the Phyllostachys clade, Arundinaria fargesii, the Ampelocalamus clade, the Fargesia grossa clade, and the Fargesia macclureana clade, were identified. Molecular phylogenetic analyses supported that Yushania should be included in Fargesia (s.l.) which had synapomorphy of expanded leaf sheaths in varying degree at the basis of inflorescences, and further divided into the Fargesia spathe clade, the Fargesia grossa clade, and the Fargesia macclureana clade. All sampled species of Yushania were nested within the Fargesia grossa clade. The probable model of the origin of the species in the Fargesia spathe clade with spathe-like leaf sheath syndrome was proposed. Moreover, the formation of the spathe-like leaf sheath syndrome may be correlated with cold climatic conditions in Quaternary. Our results provide new sight into the phylogenetic relationship within Fargesia.


Degradation of Orange II in aqueous solution by a novel electro/Fe3O4 process.
The removal of Orange II in aqueous solution by Fe3O4 enhanced anode oxidation (EC/Fe3O4 process) was performed in an electrochemical reactor. The process involved the use of a dimensionally stable anode and a stainless steel cathode. Fe3O4 was performed as particle electrodes to increase mass transfer coefficient and reduce energy consumption. Various parameters were investigated to optimize the process, including initial pH, Fe3O4 dosage and current density. The results indicated that the decolorization of Orange II followed pseudo first-order kinetics. The decolorization was favorable in acidic media than in neutral or alkaline solution, while it increased with the Fe3O4 dosage and current density. The total organic carbon (TOC) removal efficiency was 33.2% after 120 min reaction. The X-ray photoelectron spectroscopy was applied to investigate the surface properties of Fe3O4 before and after reaction.


Urn models for response-adaptive randomized designs: a simulation study based on a non-adaptive randomized trial.
Recently, response-adaptive designs have been proposed in randomized clinical trials to achieve ethical and/or cost advantages by using sequential accrual information collected during the trial to dynamically update the probabilities of treatment assignments. In this context, urn models-where the probability to assign patients to treatments is interpreted as the proportion of balls of different colors available in a virtual urn-have been used as response-adaptive randomization rules. We propose the use of Randomly Reinforced Urn (RRU) models in a simulation study based on a published randomized clinical trial on the efficacy of home enteral nutrition in cancer patients after major gastrointestinal surgery. We compare results with the RRU design with those previously published with the non-adaptive approach. We also provide a code written with the R software to implement the RRU design in practice. In detail, we simulate 10,000 trials based on the RRU model in three set-ups of different total sample sizes. We report information on the number of patients allocated to the inferior treatment and on the empirical power of the t-test for the treatment coefficient in the ANOVA model. We carry out a sensitivity analysis to assess the effect of different urn compositions. For each sample size, in approximately 75% of the simulation runs, the number of patients allocated to the inferior treatment by the RRU design is lower, as compared to the non-adaptive design. The empirical power of the t-test for the treatment effect is similar in the two designs.


Benefit Duration and Return to Work Outcomes in Short Term Disability Insurance Programs: Evidence from Temporary Disability Insurance Program.
Purpose The Workforce Innovation and Opportunity Act strengthens the vocational rehabilitation program's focus on providing early intervention services to keep workers with disabilities in the workforce. At the same time, some have suggested that short-term disability insurance (STDI) programs may hold promise as an early intervention service, helping people with disabilities stay in the labor force and avoid needing longer-term benefits. Rhode Island is one of five states with a mandatory STDI program. We examine the extent to which Rhode Island STDI claimant characteristics are correlated with partial return-to-work (PRTW) benefit receipt and certain STDI benefit receipt duration measures.Methods Our study used administrative data from 2011 to 2014 to explore Rhode Island's STDI program-called the Temporary Disability Insurance program-and regression analysis to estimate the correlations of interest. Results Regression adjusted estimates revealed that claimants opting to receive PRTW benefits earned more and received benefits for fewer weeks than claimants opting to not receive PRTW benefits. We also observed significant correlations between duration of benefit receipt and claimant characteristics such as diagnosis and treating healthcare provider specialty. Conclusions Findings suggest that STDI claimants with certain characteristics are more likely to receive benefits for a long duration or not receive PRTW benefits, signaling that they might benefit from early Vocational Rehabilitation supports and services that would allow them to remain productive members of the workforce and avoid long term benefit receipt.


Accuracy of Noncontrast Quiescent-Interval Single-Shot Lower Extremity MR Angiography Versus CT Angiography for Diagnosis of Peripheral Artery Disease: Comparison With Digital Subtraction Angiography.
This study sought to evaluate the image quality and diagnostic accuracy of noncontrast quiescent-interval single-shot (QISS) magnetic resonance angiography (MRA) versus iodine-contrast computed tomography angiography (CTA) in patients with peripheral artery disease (PAD), with invasive digital subtraction angiography (DSA) as the reference standard. QISS is a recently introduced noncontrast MRA technique. Although the diagnostic accuracy of QISS is reportedly similar to that of contrast-enhanced MRA, its performance compared with contrast-enhanced CTA, the most frequently used noninvasive modality for evaluation of PAD, is unknown. Thirty patients (66 ± 7 years of age) with PAD underwent lower extremity CTA with third-generation dual-source dual-energy CT and 1.5-T MRA using a prototype noncontrast QISS sequence. DSA was performed within 50 days. The abdominal aorta and lower extremity run-off were imaged. Eighteen arterial segments were analyzed. Subjective image quality (3-point Likert scale) and stenosis (5-point grading) were evaluated by 2 observers and compared using the Mann-Whitney U and chi-square tests, respectively. Sensitivity and specificity of MRA and CTA for >50% stenosis detection were compared using the McNemar-test. Of 540 segments, 15 (2.8%) and 42 (7.8%) inconclusive segments were excluded from MRA and CTA analysis, respectively (p = 0.0006). The DSA results were available for 410 of the remaining segments. Overall subjective image quality was rated similarly with QISS-MRA (2.52 [95% confidence interval: 2.46 to 2.57]) and CTA (2.49 [95% confidence interval: 2.43 to 2.55]; p = 0.5062). The sensitivity and specificity of MRA for >50% stenosis were 84.9% and 97.2%, respectively, similar to those of CTA (87.3% and 95.4%, respectively). Interobserver agreement for stenosis detection was excellent for MRA (κ > 0.81) and CTA (κ > 0.81). Noncontrast QISS-MRA provides high diagnostic accuracy compared with DSA, while being less prone to image artifacts than CTA. QISS better visualizes heavily calcified segments with impaired flow. QISS-MRA obviates the need for contrast administration in PAD patients.


Neural differences between chromatic- and luminance-driven attentional salience in visual search.
Previous electroencephalographic research on attentional salience did not fully capture the complexities of low-level vision, which relies on both cone-opponent chromatic and cone-additive luminance mechanisms. We systematically varied color and luminance contrast using a visual search task for a higher contrast target to assess the degree to which the salience-computing attentional mechanisms are constrained by low-level visual inputs. In our first experiment, stimuli were defined by contrast that isolated chromatic or luminance mechanisms. In our second experiment, targets were defined by contrasts that isolated or combined achromatic and chromatic mechanisms. In both experiments, event-related potential waveforms contralateral and ipsilateral to the target were qualitatively different for chromatic- compared to luminance-defined stimuli. The same was true of the difference waves computed from these waveforms, with isoluminant stimuli eliciting a mid-latency posterior contralateral negativity (PCN) component and achromatic stimuli eliciting a complex of multiple components, including an early posterior contralateral positivity followed by a late-latency PCN. Combining color with luminance resulted in waveform and difference wave patterns equivalent to those of achromatic stimuli. When large levels of chromaticity contrast were added to targets with small levels of luminance contrast, PCN latency was speeded. In conclusion, the mechanisms underlying attentional salience are constrained by the low-level inputs they receive. Furthermore, speeded PCN latencies for stimuli that combine color and luminance signals compared to stimuli that contain luminance alone demonstrate that color and luminance channels are integrated during pre-attentive visual processing, before top-down allocation of attention is triggered.


Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss.
Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. 1-3). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood1-3. Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system4. Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15.